Respective contributions of α‐adrenergic and non‐adrenergic mechanisms in the hypotensive effect of imidazoline‐like drugs

The hypotensive effect of imidazoline‐like drugs, such as clonidine, was first attributed to the exclusive stimulation of central α2‐adrenoceptors (α2ARs). However, a body of evidence suggests that non‐adrenergic mechanisms may also account for this hypotension. This work aims (i) to check whether imidazoline‐like drugs with no α2‐adrenergic agonist activity may alter blood pressure (BP) and (ii) to seek a possible interaction between such a drug and an α2ARs agonist α‐methylnoradrenaline (α‐MNA). We selected S23515 and S23757, two imidazoline‐like drugs with negligible affinities and activities at α2ARs but with high affinities for non‐adrenergic imidazoline binding sites (IBS). S23515 decreased BP dose‐dependently (−27±5% maximal effect) when administered intracisternally (i.c.) to anaesthetized rabbits. The hypotension induced by S23515 (100 μg kg−1 i.c.) was prevented by S23757 (1 mg kg−1 i.c.) and efaroxan (10 μg kg−1 i.c.), while these compounds, devoid of haemodynamic action by themselves, did not alter the hypotensive effect of α‐MNA (3 and 30 μg kg−1 i.c.). Moreover, the α2ARs antagonist rauwolscine (3 μg kg−1 i.c.) did not prevent the effect of S23515. Finally, whilst 3 μg kg−1 of S23515 or 0.5 μg kg−1 of α‐MNA had weak hypotensive effects, the sequential i.c. administration of these two drugs induced a marked hypotension (−23±2%). These results indicate that an imidazoline‐like drug with no α2‐adrenergic properties lowers BP and interacts synergistically with an α2ARs agonist. British Journal of Pharmacology (2001) 133, 261–266; doi:10.1038/sj.bjp.0704080